Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid–induced apoptosis of human sebaceous gland cells

Abstract

13-cis retinoic acid (13-cis RA; also known as isotretinoin) is the most potent agent available for treatment of acne. It is known that the drug induces apoptosis in cells cultured from human sebaceous glands, but its mechanism of action has not been determined. In this study, skin biopsies were taken from 7 patients with acne prior to and at 1 week of treatment with 13-cis RA. TUNEL staining confirmed that 13-cis RA induced apoptosis in sebaceous glands. Transcriptional profiling of patient skin and cultured human sebaceous gland cells (SEB-1 sebocytes) indicated that lipocalin 2 was among the genes most highly upregulated by 13-cis RA. Lipocalin 2 encodes neutrophil gelatinase-associated lipocalin (NGAL), which functions in innate immune defense and induces apoptosis of murine B lymphocytes. Increased immunolocalization of NGAL was noted in patients' sebaceous glands following treatment with 13-cis RA, and recombinant NGAL induced apoptosis in SEB-1 sebocytes. Furthermore, apoptosis in response to 13-cis RA was inhibited in the presence of siRNA to lipocalin 2. These data indicate that NGAL mediates the apoptotic effect of 13-cis RA and suggest that agents that selectively induce NGAL expression in sebaceous glands might represent therapeutic alternatives to the use of 13-cis RA to treat individuals with acne.

Early gene changes induced by isotretinoin in the skin provide clues to its mechanism of action

“…Detailed studies of NGAL's localization and function within the sebaceous gland demonstrated that NGAL mediates the apoptotic action of 13-cis RA on sebaceous glands, thereby suggesting that agents which selectively induce NGAL expression in sebaceous glands might represent therapeutic alternatives to the use of 13-cis RA for the treatment of acne. 1 In addition to NGAL, 13-cis RA affected the expression of numerous other genes in patient skin at one-week and in our sebocyte cell culture model, SEB-1. The results of these gene expression array analyses have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus Database and are available under series accession number GSE10434.…”

Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action

“…1B and C). 1 Significant decreases in expression of genes that regulate lipid metabolism were noted after 8 weeks of isotretinoin therapy. Gene array expression analysis was performed on patient skin biopsies at baseline and at 8 weeks of isotretinoin therapy in order to gain insight into putative pathways affected by 13-cis RA treatment.…”

“…These data were compared to results from the array analysis and histology of skin from patients treated for one week as has recently been reported. 1 Distinctly different patterns of gene expression were noted depending upon the duration of therapy. In particular, marked decreases in the expression of genes involved in lipid metabolism were found at 8 weeks, which is in agreement with the marked decrease in sebaceous gland size.…”

“…This contrasts with the significant increases in genes encoding differentiation markers, tumor suppressors, serine proteases and serine protease inhibitors observed at 1 week of isotretinoin therapy. 1 By examining the changes in individual gene expression using bioinformatics to identify enriched protein domains, chromosomal locations and cellular pathways and to analyze gene promoters that are preferentially influenced by isotretinoin, we hope to gain a greater understanding of isotretinoin's influence on the entire cell. Furthermore, a comparison between the changes in gene expression at 1 week and 8 weeks of treatment allows us to appreciate the complexity of changes that occur in the skin during the course of therapy.…”

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

“…lcn2 is also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL) (Borregaard and Cowland, 2006). In vitro studies have shown that lcn2 is important for both cellular apoptosis and survival (Devireddy et al, 2001(Devireddy et al, , 2005Yousefi and Simon, 2002;Tong et al, 2003Tong et al, , 2005Nelson et al, 2008). It also plays an important role in the induction of cellular differentiation in kidney during embryogenesis (Yang et al, 2002) and protects the kidney from ischemic injury (Mishra et al, 2004;Mori et al, 2005).…”